Protective effect of recombinant adeno-associated virus 2/8-mediated gene therapy from the maternal hyperphenylalaninemia in offsprings of a mouse model of phenylketonuria.
Phenylketonuria (PKU) is an autosomal recessively inherited metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and the fetus of an uncontrolled pregnant female patient presents with maternal PKU syndrome. We have reported previously on the cognitive outcome of biochemical and phenotypic reversal of PKU in a mouse model, Pahenu2, by the AAV serotype 2-mediated gene delivery of a human PAH transgene. However, the therapeutic efficacy had been limited to only male PKU mice. In this study, we generated a pseudotyped recombinant AAV2/8-hPAH vector and infused it into female PKU mice through the hepatic portal vein or tail vein. Two weeks after injection, complete fur color change to black was observed in female PKU, as in males. The PAH activity in the liver increased to 65-70% of the wild-type activity in female PKU mice and to 90% in male PKU mice. Plasma phenylalanine concentration in female PKU mice decreased to the normal value. In addition, the offsprings of the treated female PKU mice can rescue from the harmful effect of maternal hyperphenylalaninemia. These results indicate that recombinant AAV2/8-mediated gene therapy is a potential therapeutic strategy for PKU.
Jung
Sung-Chul
SC
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea. jungsc@ewha.ac.kr
Park
Joo-Won
JW
Oh
Hyun-Jeong
HJ
Choi
Jin-Ok
JO
Seo
Kyung-In
KI
Park
Eun-Sook
ES
Park
Hae-Young
HY
D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010661:Phenylketonurias / Q000235:genetics* / Q000628:therapy*; D011994:Recombinant Proteins / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors
D011994:Recombinant Proteins